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Blood, 15 September 2000, Vol. 96, No. 6, pp. 2134-2139
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
ADP induces partial platelet aggregation without shape change and
potentiates collagen-induced aggregation in the absence of
G q
Philippe Ohlmann,
Anita Eckly,
Monique Freund,
Jean-Pierre Cazenave,
Stefan Offermanns, and
Christian Gachet
From INSERM U.311, Etablissement Français
du Sang-Alsace, Strasbourg, France, and Institut für
Pharmakologie, Freie Universität Berlin, Berlin, Germany.
Platelets from G q knockout mice are unable to aggregate in
response to physiological agonists like adenosine
5'-diphosphate (ADP), thromboxane A2, thrombin, or
collagen, although shape change still occurs in response to all of
these agonists except ADP. ADP-induced platelet aggregation results
from simultaneous activation of the purinergic P2Y1
receptor coupled to calcium mobilization and shape change and of a
distinct P2 receptor, P2cyc, coupled through Gi to adenylyl cyclase
inhibition, which is responsible for completion and amplification of
the response. P2cyc could be the molecular target of the antithrombotic
drug clopidogrel and the adenosine triphosphate (ATP) analogs
AR-C69931MX, AR-C67085, and AR-C66096. The aim of the
present study was to determine whether externally added ADP could still
act through the Gi pathway in Gq-deficient mouse platelets and
thereby amplify the residual responses to agonists such as thrombin or
collagen. It was found that (1) ADP and adrenaline still inhibited
cyclic AMP accumulation in Gq-deficient platelets; (2) both agonists
restored collagen- but not thrombin-induced aggregation in
these platelets; (3) the effects of ADP were selectively inhibited in
vitro by the ATP analog AR-C69931MX and ex vivo by clopidogrel and
hence were apparently mediated by the P2cyc receptor; and (4) high
concentrations of ADP (100 µmol/L) induced aggregation without shape
change in Gq-deficient platelets through activation of P2cyc. Since
adrenaline was not able to induce platelet aggregation even at high
concentrations, we conclude that the effects of ADP mediated by P2cyc
are not restricted to the inhibition of adenylyl cyclase
through Gi2.
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